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Pioglitazone in adult rats reverses immediate postnatal overfeeding-induced metabolic, hormonal, and inflammatory alterations

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Abstract

Immediate postnatal overfeeding in rats, obtained by reducing the litter size, results in early-onset obesity. Such experimental paradigm programs overweight, insulin resistance, dyslipidemia, increased adipose glucocorticoid metabolism [up-regulation of glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)], and overexpression of proinflammatory cytokines in mesenteric adipose tissue (MAT) in adulthood. We studied the effects of pioglitazone, a PPARγ agonist, treatment on the above-mentioned overfeeding-induced alterations. Nine-month-old rats normofed or overfed during the immediate postnatal period were given pioglitazone (3 mg/kg/day) for 6 weeks. Pioglitazone stimulated weight gain and induced a redistribution of adipose tissue toward epididymal location with enhanced plasma adiponectin. Treatment normalized postnatal overfeeding-induced metabolic alterations (increased fasting insulinemia and free fatty acids) and mesenteric overexpression of GR, 11β-HSD11, CD 68, and proinflammatory cytokines mRNAs, including plasminogen-activator inhibitor type 1. Mesenteric GR mRNA levels correlated positively with mesenteric proinflammatory cytokines mRNA concentrations. In vitro incubation of MAT obtained from overfed rats demonstrated that pioglitazone induced a down-regulation of GR gene expression and normalized glucocorticoid-induced stimulation of 11β-HSD1 and plasminogen-activator inhibitor type 1 mRNAs. Our data show for the first time that the metabolic, endocrine, and inflammatory alterations induced by early-onset postnatal obesity can be reversed by pioglitazone at the adulthood. They demonstrate that pioglitazone, in addition to its well-established effect on adipose tissue redistribution and adiponectin secretion, reverses programing-induced adipose GR, 11β-HSD1, and proinflammatory cytokines overexpression, possibly through a GR-dependent mechanism.

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Authors and Affiliations

  1. Aix-Marseille Univ, Faculté de Médecine, 13385, Marseille, France

    S. Boullu-Ciocca, V. Tassistro, A. Dutour & M. Grino

  2. Inserm, UMR1062, “Nutrition, Obesity and Risk of Thrombosis”, 13385, Marseille, France

    V. Tassistro, A. Dutour & M. Grino

  3. INRA, UMR1260, 13385, Marseille, France

    V. Tassistro, A. Dutour & M. Grino

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  1. S. Boullu-Ciocca
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Correspondence to M. Grino.

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Boullu-Ciocca, S., Tassistro, V., Dutour, A. et al. Pioglitazone in adult rats reverses immediate postnatal overfeeding-induced metabolic, hormonal, and inflammatory alterations. Endocrine 50, 608–619 (2015). https://doi.org/10.1007/s12020-015-0657-z

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